Cataracts are the leading cause of blindness in the world, affecting nearly 20.5 million Americans age 40 and older. Most cataracts appear with advancing age; however, the etiology and pathogenesis remain poorly understood. Based on our preliminary studies, age-related cataracts also are very common in mice. At The Jackson Laboratory (TJL), we have just completed a research project to screen aged mice from 35 strains for models of human age-related ocular diseases. This project identified 21 strains of mice with cataracts ranging in age of onset from 8 to 22 months of age. Another 14 strains of mice had clear lenses throughout their lives. Since these 35 strains of mice are all inbred so that the individuals are identical within a strain and all mice are maintained in the same standard environment, these results provide strong evidence that genetic mechanisms contribute to the etiology and pathogenesis of age-related mouse cataracts. The laboratory mouse has become the preeminent model organism for understanding mammalian physiology and genetics for many reasons, including the extensive genetic resources available and the ability to add genes via transgenesis as well as delete them via targeted mutagenesis. This utility has been emphasized with analyses of the human and mouse genome sequences demonstrating that we share over 99% of our genes with mice and that these genes are arranged in a parallel fashion on chromosomes, making it possible to cross-identify genes of interest. Using the mouse as a model, we can focus on the underlying genetic causes by controlling variance due to environmental factors and test environmental factors by altering them in a controlled way. In this research proposal, we will use 21 C57BL/6J-Chr#A chromosome substitution (consomic) strains (mice of the B6 host strain develop age-related cataracts; mice of the A/J donor strain do not) and two parental strains to test the hypothesis that genetic mechanisms contribute to the etiology and pathogenesis of age-related cataracts by phenotyping aged mice of the 21 consomic strains. We will also characterize age-related cataracts in B6 mice and perform genome array analysis of global gene expression differences between lenses with age-related cataracts (B6) and clear lenses (A/J and at least one of the CSS strains in which mice do not develop cataracts).